Project 1 Abstract An effective HIV vaccine remains an elusive goal. The possible limited success of the RV144 vaccine trial supports that it is possible to provide protection from HIV acquisition through immunization. However, the vaccine-induced responses elicited by the RV144 ALVAC vCP1521-AIDSVAX B/E strategy were modest and of limited durability. The immune responses induced in a preferred vaccine should be superior to those observed in RV-144 (low T cells, limted antibodies, partially effective) as well as STEP and HVTN 505 (limited antibody responses, non effective T cell responses). A vaccine platform that avoids induction of anti-vector immunity is of growing importance in light of possible enhancement issues. Currently, there is no such HIV vaccine available, and few groups have the combination of technologies proven in the clinic to produce such a platform. This innovative program makes major advances in new DNA adaptive EP + gene adjvuant vaccine technology which in the clinic generates T cell immunity equivalent or superior to live viral vector vaccines (30, 2). We will build on this recent clinical success by novel genetic adjuvants focused on improved antibody induction as well as next generation adaptive EP focusing on skin delivery. We concentrate on increasing the breadth of coverage induced by these designed DNA vaccine by exploring the potential of a multivalent DNA prime followed by a multivalent protein boost. Furthermore, we plan to develop this collection of technologies in a simplified vaccine scheme that has distinct clinical advantages for global testing. There are three aims that comprise this program.